Using the anticonvulsant carbamazepine, we have documented acute response in approximately two-thirds of acutely manic patients and one-third of acutely depressed patients. Lithium augmentation of inadequate response is also observed, in spite of greater decrements in T3 and T4 than with either agent alone. Long-term prophylaxis has also been documented with carbamazepine, although a subgroup of patients show loss of efficacy over time. This may represent the development of tolerance and appears to occur in patients with the most rapidly deteriorating prior course of illness. Patients who are inadequately responsive to carbamazepine may respond to valproate and vice versa. Thus, carbamazepine and valproate appear to be important clinical options in treatment-refractory bipolar illness. Good responses have not been observed to the anticonvulsant phenytoin, while clonazepam may be useful for breakthrough manic episodes and their associated insomnia. A clinical trial of the anticonvulsant calcium channel blocker nimodipine has been instituted. We are attempting to discern clini- cal and biological markers of differential response to lithium and different anticonvulsant agents.